Faculty Collaboration Database

Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor. Proc Natl Acad Sci U S A 2011 Sep 27;108(39):16212-6

Date

09/13/2011

Pubmed ID

21908710

Pubmed Central ID

PMC3182712

DOI

10.1073/pnas.1100012108

Scopus ID

2-s2.0-80053645046 (requires institutional sign-in at Scopus site)   87 Citations

Abstract

The 14-3-3 family of phosphoserine/threonine-recognition proteins engage multiple nodes in signaling networks that control diverse physiological and pathophysiological functions and have emerged as promising therapeutic targets for such diseases as cancer and neurodegenerative disorders. Thus, small molecule modulators of 14-3-3 are much needed agents for chemical biology investigations and therapeutic development. To analyze 14-3-3 function and modulate its activity, we conducted a chemical screen and identified 4-[(2Z)-2-[4-formyl-6-methyl-5-oxo-3-(phosphonatooxymethyl)pyridin-2-ylidene]hydrazinyl]benzoate as a 14-3-3 inhibitor, which we termed FOBISIN (FOurteen-three-three BInding Small molecule INhibitor) 101. FOBISIN101 effectively blocked the binding of 14-3-3 with Raf-1 and proline-rich AKT substrate, 40 kD(a) and neutralized the ability of 14-3-3 to activate exoenzyme S ADP-ribosyltransferase. To provide a mechanistic basis for 14-3-3 inhibition, the crystal structure of 14-3-3ζ in complex with FOBISIN101 was solved. Unexpectedly, the double bond linking the pyridoxal-phosphate and benzoate moieties was reduced by X-rays to create a covalent linkage of the pyridoxal-phosphate moiety to lysine 120 in the binding groove of 14-3-3, leading to persistent 14-3-3 inactivation. We suggest that FOBISIN101-like molecules could be developed as an entirely unique class of 14-3-3 inhibitors, which may serve as radiation-triggered therapeutic agents for the treatment of 14-3-3-mediated diseases, such as cancer.

Author List

Zhao J, Du Y, Horton JR, Upadhyay AK, Lou B, Bai Y, Zhang X, Du L, Li M, Wang B, Zhang L, Barbieri JT, Khuri FR, Cheng X, Fu H

Author

Joseph T. Barbieri PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

14-3-3 Proteins
Animals
COS Cells
Crystallography, X-Ray
Enzyme-Linked Immunosorbent Assay
Fluorescence Polarization
Models, Molecular
Protein Binding
Protein Conformation
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization